Self-pollination, style length development and seed set in self-compatible Asteraceae: evidence from Senecio vulgaris L.

The work was supported in part by the Natural Environment Research Council under Grants [(GR3/6203A; GR9/1782A] to RJA.Background: Variation in style length has been reported in Senecio vulgaris and has been associated with outcrossing rate. Aims: To determine if (i) long styles lack germinated pollen on stigmas left to self-pollinate, (ii) successful self-pollination causes styles to stop elongating and shrink in length and (iii) seed set increases with the amount of pollen deposited on stigmas. Methods: Determined germinated self-pollen on stigmas of long and short styles after auto-self-pollination; scored style length over 48 h in self-pollinated and non-pollinated florets; recorded seed set after placing different amounts of pollen on stigmas. Results: Most long-styled florets had zero or low amounts of germinated pollen on stigmas in contrast to most short-styled florets. Styles initially elongated to the same length in self-pollinated and non-pollinated florets, then shrank in length in self-pollinated florets while continuing to elongate in non-pollinated florets. Seed set increased with number of pollen grains deposited on stigmas. Conclusions: Successful self-pollen deposition and/or germination on stigmas of S. vulgaris are indicated by presence of short styles, whereas the opposite is indicated by presence of long styles in florets left to self-pollinate. Self-pollination causes styles to shrink after initially elongating. Seed set is dependent on the amount of pollen deposited on stigmas.Publisher PDFPeer reviewe

Permeable, Non-irritating Prodrugs of Nonsteroidal and Steroidal Agents

Prodrugs containing an active drug molecule linked to a polyethylene glycol group, and a method of use thereof are described. Exemplary soluble ester prodrugs contain naproxen, triamcinolone acetonide, gancyclovir, taxol, cyclosporin, dideoxyinosine, trihydroxy steroids, and flurbiprofen molecules linked to polyethylene glycol (PEG) groups. Pharmaceutical compositions containing these prodrugs, and a method of using these esters for treating disease states or symptoms are also described

Prosocial Spending and Well-Being: Cross-Cultural Evidence for a Psychological Universal

This research provides the first support for a possible psychological universal: human beings around the world derive emotional benefits from using their financial resources to help others (prosocial spending). Analyzing survey data from 136 countries, we show that prosocial spending is consistently associated with greater happiness. To test for causality, we conduct experiments within two very different countries (Canada and Uganda) and show that spending money on others has a consistent, causal impact on happiness. In contrast to traditional economic thought—which places self-interest as the guiding principle of human motivation—our findings suggest that the reward experienced from helping others may be deeply ingrained in human nature, emerging in diverse cultural and economic contexts.

Vestiges of the Phoenix: De Quincey, Kant and the Heavens

© Edinburgh University Press, 2011publication-status: Accepte

BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells

SummaryMost forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation

Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease

INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid-beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aβ42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. HIGHLIGHTS: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aβ42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden

A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant

OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions

The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia

New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders

Rethinking Epistemic Relativism

‘Relativism’ is often treated as a dirty word in philosophy. Showing that a view entails relativism is almost always considered tantamount to showing that it is nonsensical. However, relativistic theories are not entirely unappealing – they have features which might be tempting if they weren’t thought to be outweighed by problematic consequences. In this paper I argue that it’s possible to secure the intuitively appealing features of at least one kind of relativism – epistemic relativism – without having to accept any problematic consequences. I do this by defending what I call 'stratified relativism'